Approximately two thirds of patients with intrahepatic cancer present with unresectable disease. Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by the development of radiation-induced liver disease (RILD). The pathology of RILD is veno-occlusive disease, which is characterized by thrombosis within the central veins of the liver producing post hepatic congestion. In the past, efforts to develop models to estimate the likelihood of developing RILD have been based primarily on the planned radiation dose distribution for the normal liver. These analyses have demonstrated that increasing mean liver dose correlates with the likelihood of developing RILD. While these models have permitted the safe delivery of far higher doses of radiation than have previously been possible, they also suggest that there is a broad range of individual patient sensitivity that is not reflected by predictions made solely based on the physical dose distribution or general clinical features. As the basic pathophysiology of RILD is venous occlusion, we develop the hypothesis that early monitoring of portal venous perfusion and hepatobiliary function would have the potential to predict liver function after irradiation, thereby permitting to safely deliver the higher dose to the tumor without an increase of complications. Our preliminary data provide evidence to support this hypothesis. In this R01 application, we propose to develop a model to predict liver function after the completion of radiation therapy based upon the radiation treatment plan, and the values of portal venous perfusion and hepatobiliary function assessed by DCE MRI and SPECT prior to and during radiation therapy. Also, we assess individual and regional radiation sensitivity during radiation therapy using the liver dose response function that we have developed, for prediction of liver function after irradiation. Our proposed approach is highly innovative and represents a new paradigm to investigate radiation toxicity in the liver. It has potential to be a tool for individualized therapy. PUBLIC HEALTH RELEVANCE: Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by radiation-induced liver injury. Our long term goal is to develop a new imaging approach for prediction of radiation-induced syptomatic liver injury. Therefore, higher dose of radiation can be safely delivered to tumor in patients who can be better tolerant to radiation, thereby improving survival.